The gastrointestinal tract plays a critical role in the immunopathogenesis of HIV-1 infection. In homosexual men and nursing infants, intestinal mucosa provides access for virus entry into the host. Moreover, as the largest lymphoid organ in the body, the gastrointestinal tract mucosa is an important reservoir for virus-infected cells, and, because of the abundance of local stimulatory factors, an important site for viral transcription. These events lead to local immunosuppression and secondary opportunistic infections of the gastrointestinal tract in 50% to 90% of HlV-1-infected persons. Immunobiological events involving HIV-1 in the mucosa are presumed to be similar to those that occur in the systemic circulation. This notion may be incorrect, however, since in many ways the mucosal immune system is distinct from the systemic immune system. Moreover, there is no experimental data to confirm this notion due to the difficulty in obtaining mucosal cells. In contrast, our newly developed technique for the isolation and purification of large numbers of mucosal macrophages and lymphocytes will allow us to investigate, for the first time, the interaction between HIV-1 and the relevant cells of the gastrointestinal tract. Therefore, the overall objective of this proposal is to elucidate the role of mucosal lymphoid cells in the immunobiology of HIV-I infection of the gastrointestinal tract mucosa. The specific aims are to: 1.) Infect isolated human lamina propria macrophages with HIV-1 and determine whether viral tropism is involved in infection by comparing infection by the macrophage-tropic isolate HIV-1(Ba-l) with infection by lymphocyte-tropic isolates, tissue-specific (e.g., brain) isolates, and isolates to be derived from mucosal specimens; 2.) Determine whether HIV-1 impairs lamina propria macrophage function by comparing infected and uninfected lamina propria macrophages for accessory cell activity, cytotoxicity, and cytokine production; 3.) Determine whether mucosal epithelial cells and lamina propria lymphocytes, cell, populations which are removed in step- wise fashion during the purification of the lamina propria macrophages, can be infected with HIV-1 and whether tropism influences infection of these cells; and 4.) Determine whether secretory lgA directed against HIV- 1 enhances HlV-1 infection of lamina propria macrophages and whether locally produced cytokines, such as TNF-alpha and lL-6, and bacterial products, such as LPS and non-LPS-containing bacterial components, enhance viral transcription. These studies will document whether resident lamina propria macrophages and lymphocytes can be infected with HIV-1; show whether HIV-1 impairs mucosal macrophage function; resolve the controversy over whether HIV-1 infects epithelial cells; and elucidate the role of mucosal factors in regulating local viral transcription.